Cannabis contains more than 460 compounds of which around 70 are considered as phytocannabinoids. Hempseed oil also contains the phytcannabinoid cannabidiol (CBD). Cannabis-based medications have been intensely studied since the endogenous cannabinoid system was discovered two decades ago. Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors CB1 and CB2. Cannabinoids produce numerous therapeutic effects. They have antispastic, analgesic, antiemetic, neuroprotective, and anti-inflammatory actions. They are an effective treatment against certain psychiatric diseases.
Emerging clinical applications for cannabinoid therapies include Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), atherosclerosis, chronic pain, Diabetes mellitus, dystonia, epilepsy, fibromyalgia, gastrointestinal disorders, gliomas, cancer, Hepatitis C, Human Immunodeficiency Virus (HIV), Huntington Disease hypertension, incontinence, methicillin-resistant Staphyloccus aureus (MRSA), multiple sclerosis, osteoporosis, post-traumatic stress disorders (PTSD), pruritus, rheumatoid arthritis, sleep apnea and Tourette Syndrome.
One of the primary adverse effects of cannabinoid therapies in humans is disruption of short-term memory. That is consistent with the abundance of CB1 receptors in the hippocampus, the brain region most closely associated with memory. Cannabinoids impinge on the central nervous system by attaching to brain's neurons and interfering with normal communication between the neurons. These nerves respond by altering their initial behavior.
The most psychoactive phytocannabinoid in cannabis, Delta-9-Tetrahydrocannabinol 1 (THC), alters the way information is processed by the hippocampus, the part of the brain that is important for memory, learning, and the integration of sensory experiences with emotions and motivation. The hippocampus converts information into short-term memory. THC acts on the hippocampus and inhibits memory retrieval and how sensory information is interpreted. When THC attaches to CB1 receptors in the hippocampus, it weakens the short-term memory and creates structural changes to the hippocampus region of the brain. With high dosages, new information does not register into the brain and this may be lost from memory and they are not able to retrieve new information for more than a few minutes. Cannabinoid induced memory defects may, in part, be due to a reduction in acetylcholine release causing cholinergic hypofunction. THC reduces both extracellular and intracellular hippocampal acetylcholine concentrations.
The phytocannabinoid THC in cannabis may impair cognitive functions on a number of levels—from basic motor coordination to complex executive function tasks, such as the ability to plan, organize, solve problems, make decisions, remember, and control emotions and behavior. Acute exposure impairs inhibition, promotes impulsivity and impairs working memory. Residual deficit effects over a period of abstinence are most evident in tasks that require concept formation, planning and sequencing abilities. Emotional impairments are attributed to the way canabinoids affects the brain's limbic system.
The phytocannabinoids in cannabis may produce adverse cardiovascular effects A consistent effect from the phytocannabinoids in cannabis is increased heart rate. They can reduce the level of exercise which can be tolerated before the onset of angina. Cannabinoids produce profound coronary and cerebral vasodilatation in vivo by activation of vascular cannabinoid CB1 receptors. Their prominent, predictable effects on the heart, including increased work-load, increased plasma volume and postural hypotension that can impose threats to the individuals' hypertension, cerebrovascular disease or coronary arteriosclerosis. High doses of cannabis measured as 15 mg of THC are shown to increase heart rate, gross motor disturbances, and can lead to panic attacks.
Cannabinoids also produce a tolerance. Prolonged exposure to phyto synthetic or endogenous cannabinoid agonists is associated with the development of tolerance for most of their pharmacological effects essentially due to adaptive down-regulation and desensitization of cannabinoid receptors.
Currently employed methods of delivery of cannabis derived cannabinoids include inhalation delivery methods of smoking, vaporization and aerosols; oral ingestion delivery methods into the GI tract of infused products, edibles, extract oils, tinctures and soft gel caps; and intraoral delivery methods to the oral mucosa via sprays and drops of cannabis as tinctures, extracts, and emulsion compositions, and cannabis containing chewing gums.
Methods of delivering hempseed derived cannabinoids include oral ingestion delivery into the GI tract of infused products, edibles extract oils, tinctures and soft gel caps and intraoral delivery to the oral mucosa via sprays and drops of cannabis as tinctures, extracts, and emulsion compositions, and chewing gums.
Inhalation delivery methods of smoking and vaporization have no reliable dosage as medicine. Bioavailability following the smoking route was reported as 2-56%, due in part to intra- and inter-subject variability in smoking dynamics, which contributes to uncertainty in dose delivery. The number, duration, and spacing of puffs, hold time, and inhalation volume, or smoking topography, greatly influences the degree of exposure and blood levels.
Oral delivery methods of ingesting extracts, infusions and edibles forms have typically a delay in the onset of their actions making it extremely difficult in ingest the correct dosage of cannabinoids. The oral absorption of THC and CBD are typically reported as 6% bioavailability to the systemic circulation after extensive first pas liver metabolism. Oral delivery is slow and unpredictable, with peak concentrations occurring 1-5 hours post dose.
Several factors account for the low oral bioavailability of cannabinoid as compared to intravenous administration. They include low solubility and dissolution, variable absorption, degradation in the stomach, and significant first-pass metabolism to active and inactive metabolites in the liver. There may be variation in potency of cannabinoid constituents from crop to crop and even in the same cannabis depending upon its, age, moisture content and methods of curing. Furthermore oral ingested products often lack accurate information of the cannabinoid content per dosage and an accurate and reliable method to regulate the dosage of cannabinoids administered.
Intraoral delivery of cannabinoids to the sublingual or buccal oral mucosa delivery by spray and drops has not demonstrated significant pharmacokinetic differences from that of oral administration. Research found no statistically significant differences in bioavailability and pharmacokinetics between similar dosages of oral administered THC and the oral mucosal spray Sativex of GW Pharma delivering 2.7 mg THC and 2.5 mg cannabidiol (CBD) per actuation as demonstrated by their comparative by Cmax, time to maximum concentration or in their AUC. If THC in Sativex was primarily absorbed through the oral mucosa, bypassing first pass metabolism in place of being swallowed, one would expect a difference between oral THC and Sativex 11-OH-THC/THC ratios. Their high ratio indicates gastric degradation and extensive first-pass metabolism; however, no statistical difference was found.
This disclosure teaches methods and compositions of cannabinoids to overcome their intrinsic low oral bioavailability, reduce cannabinoid dosages without loss of therapeutic efficacy, increase suitability for long-term or daily cannabinoid therapy and reduce cannabinoids adverse effects.
The disclosure teaches methods and delivery system compositions of cannabinoids that increase the bioavailability, bioactivity, therapeutic activity and therapeutic index of cannabinoids for cannabinoid therapy.
The disclosure teaches methods and delivery system compositions of cannabinoids in standardized precision-metered dose forms that deliver the same amounts of cannabinoids in each administration, rapidly reach the systemic circulation and maintain consistent plasma levels over time; with the ability to enable precision dispensing and create a high degree of user compliance.
The disclosure teaches methods and compositions that provide enhanced cannabinoid bioactivity, increased therapeutic activity, at lower doses and with fewer adverse actions; deliver standardized precision-metered dosage forms of cannabinoids; and administration by more effective methods of delivery, making cannabinoid drug treatments more efficacious and available to a larger number of patients.